1. Common medical emergencies and drug toxicityBy
Dr. Mohamed Abdel Moneim Attia

2. PARASYMPATHOMIMETICS (Cholinomimetics)
This group of drugs produces pharmacological effects similar to that produced by parasympathetic stimulation
Classification
1- DIRECTLY ACTING PARASYMPATHOMIMETICS
They directly stimulate the cholinergic receptors.
Choline esters:
Acetylcholine.
Carbachol.
Bethanechol
Methacholine
B. Alkaloids:
Pilocarpine.
Muscarine.

3. 2- INDIRECTLY ACTING PARASYMPATHOMIMETICS (CHOLINE ESTERASE INHIBITORS)
They inhibit cholineesterase enzymes leading to accumulation of A.ch at the receptor sites which in turn produces the cholinergic effects on (CNS, NMJ, Ganglia, wall of blood vessels... etc.).
A. Reversible cholineesterase inhibitors.
Physostigmine
Neostigmine and its substitutes.
Tacrine
Donepezil
B. Irreversible cholineesterase inhibitors.
Organophosphorous compounds.

4. ACETYLCHOLINE (A.Ch) Pharmacokinetics
A.ch is inactive orally because it is poorly absorbed being a quaternary ammonium compound. I.V. it has very short duration of action because it is rapidly metabolized by choline esterase enzymes.
True cholinesterase enzyme
Pseudocholinesterase enzyme
Site
Cholinergic nerve - CNS – RBCs
Plasma – liver – intestine
Synthesis
3 months
2-3 weeks
Specificity
specific
Not specific

5. ►Pharmacodynamics
  Mechanism of Action: act via:
Stimulation of the muscarinic receptors.
Stimulation of the nicotinic receptors.
Cholinoceptors
They are broadly subdivided into muscarinic and nicotinic receptors.

6. A. Muscarinic receptors (peripheral, M receptors)
Types:
M1 receptors:
Are present in autonomic ganglia, CNS and parietal cells of the stomach
M2 receptors:
Are present in heart.
also present presynaptically on the cholinergic fibers to inhibit acetylcholine release (feedback)
M3 receptors: are present in smooth muscle fibers and secretory glands.
M4 and M5 receptors: in the C.N.S.
B. Nicotinic receptors (central, N receptors)
►Types:
Nn (Neuronal nicotinic receptors): present in autonomic ganglia and suprarenal medulla.
Nm (Muscle nicotinic receptors): present in the neuromuscular junction.

7. Pharmacological Effects
*C.V.S
Heart:
Decreases all cardiac properties, except the conduction in the atria, which is increased.
Blood vessels: generalized vasodilatation.
Blood pressure: blood pressure is decreased.
*G.I.T:
A.ch increases gastric and intestinal peristalsis and relax the sphincters. It also stimulates salivary and gastric secretions.
*Lung:
bronchoconstriction and increased bronchial secretion.
 *Urinary tract:
A.ch contracts the detrusor muscle and relaxes the sphincter of the urinary bladder.
It increases the peristaltic waves of the ureters.
 *Eye:
A.ch produces meiosis.
►Skeletal muscles: stimulate motor end plate.

8. ►Therapeutic Uses
It has limited use because of its short duration and non-selectivity.
 ►Untoward Effects
All effects produced by A.ch are untoward effect.
 ►INDIRECTLY ACTING PARASYMPATHOMIMETICS
(Cholinesterase Inhibitors)
 ►Mechanism of action
By inhibiting cholinesterase, the indirect – acting agonists “amplify” the action of endogenous acetylcholine. Therefore, the indirect agents have muscarinic or nicotinic.

9. A- REVERSIBLE CHOLINESTERASE INHIBITORS
1- PHYSOSTIGMINE
 ►Chemistry
It is a tertiary amine
 ►Pharmacokinetics
Being a tertiary amine, it can diffuse readily through the mucous membranes.
It can cross blood brain barrier.
►Pharmacodynamics
  Mechanism of Action
Physostigmine binds to both esteratic and anionic sites of cholinesterase enzymes.
The attraction between this drug and the enzyme is 10,000 times that of Ach, but this binding is loose and the drug would dissociate gradually leaving the enzyme free.
Binding of physostigmine to cholinesterase leads to accumulation of Ach in the effector organs (CNS, NMJ, Ganglia, blood vessels and opposite the parasympathetic nerve endings).

10. Pharmacological Effects
Muscarinic effects. (See above) , Nicotinic effects. (See above)
CNS effects: headache, restlessness, insomnia, nightmares, tremors and convulsions.
►Therapeutic Uses
1-Treatment of glaucoma (locally in the eye)
2-To counteract the mydriatic effect and cycloplegia produced by atropine.
4-Treatment of atropine poisoning and tricyclic antidepressant toxicity.
5-Alzheimer disease.
Donepezil , Tacrine and Rivastigmine
Are new, centrally acting, reversible cholinesterase inhibitors that readily cross the blood–brain barrier and act to increase the concentration of acetylcholine at central cholinergic synapses. These drugs are used in the treatment of Alzheimer’s disease .
►Untoward Effects
All the muscarinic effects. (See above)
All the nicotinic effects. (See above)
All the CNS effects. (See above)

11. 2- NEOSTIGMINE (Prostigmine) ►Chemistry: It is a synthetic quaternary ammonium compound. ►Pharmacokinetics Being a quaternary ammonium compound, it is irregularly absorbed from GIT and it cannot cross the B.B.B. ►Pharmacodynamics  Mechanism of Action *Reversible inhibition of cholinesterase enzymes (Muscarinic effects and Nicotinic effects ). *Direct stimulant action on neuromuscular junctions. *It has no CNS effects.

12. ►Therapeutic Uses
1-Treatment and diagnosis of myasthenia gravis:
*S.C for diagnosis
*Oral for treatment.
2-Antidote to D-tubocurarine.
3-Treatment of postoperative retention of urine.
4-Treatment of paralytic ileus.
►Untoward Effects
All the muscarinic and nicotinic effects except that intended for therapeutic purposes.

13. 3- NEOSTIGMINE SUBSTITUTES
Neostigmine substitutes have been introduced with the advantage of being more selective on the neuromuscular junction or having a longer duration of action to be more convenient for the treatment of myasthenia gravis and other clinical purpose.
a- Pyridostigmine
 b- Ambenonium : Similar to pyridostigmine.

14. c- Edrophonium
More selective on NMJ than neostigmine.
Very short acting (5 min.)
►Uses
Diagnosis of myasthenia gravis.
Treatment of myasthenic crisis.
Differentiation between myasthenic crisis and cholinergic crisis (Weakness due to over treatment with anticholinesterase). It aggravates cholinergic crisis, but improves myasthenic crisis.
Antidote for D-tubocurarine.

15. Myasthenia Gravis
►Definition
Myasthenia gravis is a disease characterized by impaired transmission at N.M.J.
Aetiology:
Autoimmune disease due to formation of antibodies that attack the nicotinic receptors in N.M.J.
►Clinical picture
Marked weakness of skeletal muscles.
 ►Diagnosis
Edrophonium: it improves the contraction of skeletal muscles in patient with myasthenia gravis.
neostgmine but atropine is given before neostigmine because atropine produced initial bradycardia followed by tachycardia. This initial bradycardia potentiates bradycardia caused by neostigmine → cardiac arrest.

16. Choline estrase inhibitors:
►Treatment
Choline estrase inhibitors:
Ambenonium or pyridostigmine.
Neostigmine + atropine ( If ambenonium or pyridostigmine are unavailable).
Ephedrine: Facilitates transmission at N.M.J.
Immunosuppressives, corticosteroids, ACTH or cyclosporine.
Thymectomy.
Kcl & Spironolactone

17. Myasthenic crisis
Cholinergic crisis
Cause
Deficient cholinergic transmission
Excessive cholinergic transmission e.g. ch. E inhibitor overdosage.
Nicotinic manifestations
Muscarinic manifestations
Flaccid paralysis. No
Spastic paralysis. Weakness in cholinergic crisis is due to permanent depolarization of nicotinic receptors at motor end plate.
↓ H.R. – ↓ B.P. – Miosis – Colic – sweating.
Edrophonium test
Improves
Aggrevates.
Treatment
*Edrophonium or neostigmine + atropine.
*Artificial respiration
1-PAM (pralidoxime)+ Atropine
2. Artificial respiration
3. Stop causative drug

18. B- IRREVERSIBLE CHOLINESTERASE INHIBITORS ( ORGANOPHOSPHOROUS COMPOUNDS)
 Nerve gases: Sarin, Soman.
Insect killers: Malathion, Parathion, TEPP (tetraethylpyrophosphate)
Drugs used clinically: DFP (Diisopropyl flurophosphate)
►Mechanism of Action
Organophosphorous compounds bind covalently (irreversibly) to cholinesterase enzymes. In this situation the body has to replace the inactivated enzymes. This replacement takes two weeks for pseudocholine-esterase and three months for true cholinesterase. A.ch. will accumulate at the effector sites in large amounts producing parasympathomimetic effects.
Irreversible inhibition of the enzyme takes about 1-12 hrs after exposure until the complex (enzyme and organophosphorous) loses some alkyl and alkoxyl groups, a process known as aging of the enzyme (i.e. the enzyme is no more suitable for functioning). During the first 12 hrs after exposure the enzyme could be reactivated.

19. ►Pharmacological Effects (All are toxic effects)
 ►Toxicity
 The signs and symptoms of over dosage are readily predicted from the general pharmacology of acetylcholine.
Muscarinic Toxicity
These include CNS stimulation , meiosis, spasm of accommodation, bronchoconstriction, increased gastrointestinal and genitourinary smooth muscle activity, increased secretory activity (sweat glands, airway, gastrointestinal tract), vasodilatation, and bradycardia.
Nicotinic Toxicity
These include CNS stimulation, ganglionic stimulation, and neuromuscular endplate depolarization leading to fasciculation and paralysis.
Muscarinic effects. (See above)
Nicotinic effects. (See above)
CNS effects. (See above)

20. ►Untoward Effects and Toxicity
The indirect acting agents have toxicological importance because of potential accidental exposures to toxic amounts of pesticides. The most toxic of these drugs, (e.g., parathion) is rapidly fatal if exposure is not immediately recognized and treated.
Generally the clinical picture could be summarized as follows:

21. Respiratory:
Bronchospasm, respiratory distress, and paralysis of respiratory muscles.
Cardiovascular:
Bradycardia, hypotension and excessive cold sweating.
Gastrointestinal:
Excessive secretions, abdominal colic, diarrhea, vomiting,
C.N.S:
Severe meiosis, headache, irritability, skeletal muscle fasciculation.
Convulsions and coma are terminal manifestations.
The usual cause of death is respiratory failure (Bronchospasm, excessive secretions, inhibition of R.C. and contraction of the intercostal muscles and diaphragm)

22. ►Treatment of the Untoward Effects
 Protection
Farmers who spray the insecticides should wear gloves and masks.
Thorough washing of vegetables.
Glasses containing domestic insecticides should be kept away from children.
Treatment
Stomach wash.
Wash the skin, if contaminated by sodium bicarbonate or ethyl alcohol.
Maintain the air passage open by sucking secretion and start artificial respiration if needed.
Atropine in high doses:
2 mg I.V. or I.M. every minutes until the patient is put on the merge of atropine toxicity (dilated pupil, dry mouth, and tachycardia).
The patient should be kept atropinized for 24 hours.

23. The intoxicated patient may need up to 100 mg for full atropinization.
Atropine eye drops may relieve the headache caused by miosis.
Atropine will antagonize the peripheral and central effects of organophosphorous compounds, but not the action of N.M.J. and the ganglia.
The patient should be maintained on atropine until the enzymes are recovered.
*Convulsions may be controlled by anticonvulsants (diazepam).

24. Cholinesterase re-activators (oximes):
They should be given within 1/2 to 1 hr after exposure maximum 12 hrs. i.e. before aging of the enzyme.
During this period they are life saving because they react directly with the alkylphosphorylated enzyme to free the active unit (de-phosphorylation) of the enzyme.
Moreover oximes compete with the enzyme for the organophosphate i.e. (phosphorylated very easily so, they divert the poison from cholinesterase to oximes.
Preparations
Pralidoxime (PAM, Protopam): 2.5 gm in 100 ml I.V. infusion (within 30 min.), 1 gm I.M. every 1 hr until recovery. 20 mg /kg for infants and children.
Diacetylmonoximes (DAM)
Bisquaternary oxime.

25. PARASYMPATHOLYTICS (Muscarinic antagonists)
 Definition
These are drugs, which block the muscarinic receptors.
 Classification
A- Natural Alkaloids
Examples:
Atropine : extracted from Atropa belladonna plant or Datura stramonium plant.
Scopolamine (L –Hyoscine).
B- SYNTHETIC ESTERS
These are either tertiary amines (lipid soluble and cross the blood brain barrier or quaternary amines (lipid insoluble) and cannot cross the blood brain barrier).
They are classified according to their clinical uses into:

26. - Drugs mainly used to treat the manifestations of parkinson’s disease:
Benzatropine ,Trihexyphenidyl ,Biperiden.
2- Drugs mainly used to produce mydriasis and cycloplegia:
Atropine, Homatropine, Eucatropine, Cyclopentolate ,Tropicamide .
3- Drugs mainly used to produce bronchodilation:
Ipratropium, tiotropium
4- Drugs mainly used as antisecretory and antispasmodic on the GIT:
Hyoscine butylbromide ,Homatropine methyl bromide ,Propantheline
5- Drugs mainly used for its effect on the genitourinary system:
Oxybutynin, Glycopyrrolate ,Emepronium.

27. ►Pharmacokinetics of Atropine
Because it is a tertiary amine, atropine is relatively lipid soluble and readily crosses membrane barriers. The drug is well distributed into the CNS and other organs
The duration of action of normal doses is 4-8 hours except in the eye, where effects last for 72 hours longer
Pharmacological Effects
The peripheral actions of muscarinic blockers are mostly predictable effects derived from cholinoceptor blockade . These include the ocular, GI, genitourinary, and secretory effects.
The CNS effects are less predictable. Those seen at therapeutic concentrations include sedation, reduction of motion sickness, and, reduction of some of the signs of parkinsonism.
Cardiovascular effects at therapeutic doses include an initial slowing of heart rate caused by stimulation of the central vagal nucleus, followed by the tachycardia and decreased atrioventricular conduction time that would be predicted from peripheral vagal blockade.

28. ►Clinical Uses
The muscarinic blockers have several useful therapeutic applications in the central nervous system, eye, bronchi, gut, and the urinary bladder.
Cardiovascular:
Bradycardias and heart blook
Treatment of bradycardia caused by excessive beta-blockers
Treatment of reflex bradycardia caused by alpha stimulants e.g. noradrenaline
Neurological:
Motion Sickness:
scopolamine is a standard therapy for motion sickness; this drug is one of the most effective agents available for this condition.
A transdermal patch formulation is available.
Treatment of parkinsonism:
benztropine, biperiden, and trihexyphenidyle are representative of several antimuscarinic agents used in parkinsonism.

29. Eye (Local drops)
Fundus examination: Antimuscarinic drugs (Substitutes are better) are used to dilate the pupil and to paralyze accommodation.
To counteract the effect of miotics.
Iritis and iridocyclitis:
Alternatively with miotics to cut recent mild adhesions between the iris and anterior surface of the lens.
Bronchi:
Ipratropium is a quaternary antimuscarinic agent used by inhalation to reduce bronchoconstriction in asthma and chronic obstructive pulmonary disease (COPD). Although not as effective as beta gonists, ipratropium is less likely to cause cardiac arrhythmias. It has very few antimuscarinic effects outside the lungs because it is poorly absorbed and rapidly metabolized.

30. Gastrointestinal:
To relieve spasm in the G.I.T (intestinal colic, spastic colon and biliary colic)
Muscarinic blockers can also be used to reduce cramping and hypermotility in transient diarrheas.
Bladder:
Cystitis: Glycopyrrolate, and similar agents may be used to reduce urgency in mild cystitis and to reduce bladder spasms following urologic surgery.
Nocturnal enuresis: emepronium could be used for treatment of nocturnal enuresis and urinary incontinence
To releive ureteric spasm in renal colics

31. In Pre-Anaesthetic Medication
Atropine is given half an hour before the administration of the general anaesthetic to produce the following:
Decrease salivary and bronchial secretion:
This prevents or minimizes the possibility of inhalation of the salivary secretions preventing the postoperative lung infection.
The inhibition of the mucus secretion in the bronchial tree prevents the possibility of blockage of a main bronchus, which could lead to lung collapse.
Atropine protects the heart from excessive vagal tone, which sometimes occur at the beginning of the first plane of the surgical stage of anesthesia (Stage III).
Counteracts the inhibitory effect of morphine and the anaesthetic on the respiratory center.

32. ►Side Effects
Mild side effects may develop after the use of therapeutic doses for example:
Dryness of the mouth.
Skin flushing:
Children are more susceptible to develop coetaneous V.D which makes the child flushed and this is usually accompanied by slight elevation of body temperature (Due to reduction of sweating) especially in hot environments.
Retention of urine especially in patients with enlarged prostate.
Acute attack of glaucoma in patients who have or susceptible to glaucoma.
►Toxicity
A traditional mnemonic for atropine toxicity is “Dry as a bone, red as a beet, mad as a hatter “. This description reflects both predictable antimuscarinic effects and some unpredictable actions.

33. In young children
Blockade of thermoregulatory sweating may result in hyperthermia or “ atropine fever”. This is the most dangerous effect of the antimuscarinic drugs and is potentially lethal in infants.
In adults
Dryness of secretions:
The condition is described by “dry as a bone “ because sweating, salivation, and lacrimation are all significantly reduced or stopped in the elderly.
Acute angle – closure glaucoma may occur
Urinary retention is possible.
Constipation.
Blurred vision is common adverse effects in all age groups.
Full dilatation of the pupil and lost light reflex.

34. Other Toxicity
Toxicity not predictable from peripheral autonomic actions include the following: , Dry as bone, Blind as bat, red as beet, mad as hatter.
CNS effects:
CNS toxicity includes:
sedation, amnesia, and delirium or hallucinations (“mad as a hatter”)
convulsions and excitation may develop and later this excitation is followed by depression in the form of coma and the cause of death is respiratory failure.
Cardiovascular effects:
At toxic doses, intraventricualr conduction may be blocked; this action is probably not mediated by muscarinic blockade and is difficult to treat.
Dilation of the cutaneous vessels of the arms, head, neck and trunk also occurs at these doses; the resulting “atropine flush“ (“red as a beet”) may be diagnostic of overdose with these drugs.

35. Treatment of Toxicity (symptomatic)
Control of environmental temperature and application of cold baths and sponges.
Cathetrization if necessary.
Protection of the respiratory system.
Avoidance of over treatment of convulsions by barbiturates.
Physostigmine may be used to counteract the CNS effects. Can we use nesostigmine?
The lethal dose in adults is more than 0.5 gm of atropine and more than gm of scopolamine.

36. NEUROMUSCULAR BLOCKING AGENTS
The prototype non-depolarizing agent is d-tubocurarine; the prototype-depolarizing drug is succinylcholine.
►Pharmacokinetics
Succinylcholine is composed of two acetylcholine molecules linked end to end.
Succinylcholine is metabolized by plasma cholinesterase (butyrylcholinesterase or pseudocholinesterase)
It has a duration of action of only a few minutes if given as a single dose. It is given by continuous infusion if prolonged paralysis is required.
►Toxicity
1-Respiratory paralysis: succinyl choline apnea.

37. Is due to abnormal deficiency of pseudo-cholinestrase enzyme activity.
Treatment:
1-Artifecial respiration.
2-fesh plasma or blood tranfusion.
Dibucaine number: It is a test of the ability of pseudocholinestrase to metabolize succinylcholine. Dibucaine is an enzyme inhibitor, which inhibit 80% of normal enzyme and 25% of abnormal enzyme.

38. Malignant Hyperthermia (Hereditary Condition)
Multiple Triggering Mechanisms
Anesthesia
Drugs (general anesthesia, succinylcholine)
Illness & Stress
Triggering Mechanism Affects reuptake of calcium by sarcoplasmic reticulum necessary for termination of muscle contraction. It results in:
*Massive Muscle Contraction
*Excessive Lactate Production (acidosis, tachycardia, hypercarbia, hypoxemia).
*Pronounced Increase In body Temperature due to unccoupling oxidative phosphorylation.
Teatment:
1-I.V dantrolene.
Interferes with excitation-contraction coupling
Reduces release of Ca++ from the sarcoplasmic reticulum
Blocks contraction
2-cooling.
3-corecxt acidosis.